Anthrax is a lethal disease of humans and other animals caused by the gram-positive spore-forming eubacterium, Bacillus anthracis. While this disease has long been endemic to most countries, its incidence in human populations largely has been controlled. However, the worldwide prevalence of B. anthracis and the ease of culturing this lethal microbe have focused much recent attention on anthrax as an agent of bioterrorism.
The virulence of B. anthracis infection is due to the cellular effects of separate complexes formed by interaction of a carrier protein, protective antigen (PA, 83 kDa) with lethal factor (LF, 90 kDa) or edema factor (EF, 89 kDa). During infection by B. anthracis, PA binds to receptors on the surface of macrophages and is cleaved by the protease furin, releasing a 20 kDa fragment and enabling the residual receptor-bound C-terminal 63 kDa PA peptide fragment (PA63) to form heptamers and interact with LF or EF. After entering target cells by endocytosis, PA/LF and PA/EF complexes translocate across the endosomal membrane into the cytosol where they dissociate, allowing LF and EF to exert their toxic effects.
LF is a Zn++ protease that cleaves the amino terminus of all MAPK kinases and consequently is responsible for anthrax lethality. EF is a calmodulin-dependent adenylate cyclase that elevates intracellular levels of cAMP, producing profound edema as a typical clinical symptom and impairing the immune response to infection.